骨髓间质干细胞对血吸虫性肝纤维化修复作用的研究
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摘要
目的观察骨髓间质干细胞(mesenchymal stem cells, MSCs)单独使用或MSCs与吡喹酮(praziquantel, PZQ)联合应用对血吸虫性肝纤维化的修复作用。通过体内外实验探讨MSCs对血吸虫性肝纤维化的作用机制,为MSCs治疗慢性血吸虫性肝损伤提供实验依据。
方法①应用日本血吸虫尾蚴多次感染的方式建立血吸虫性肝纤维化的小鼠模型,并将小鼠分为5组：未感染对照组、PBS组、MSCs组、PZQ+PBS组、PZQ+MSCs组。在感染第9、10周,MSCs处理组每只小鼠分别给予5×105MSCs经尾静脉移植入肝损伤小鼠,PZQ处理组于感染第9周经灌胃给予300 mg/kg(?)比喹酮。②首次移植MSCs的第2、4周后分别应用ELISA和化学发光法检测血清中转化生长因子-β1 (transforming growth factor-β1, TGF-β1)和透明质酸(hyaluronic acid, HA)含量；病理切片苏木精-伊红染色法(HE)染色观察肝脏的组织学变化；Masson's三色染色观察肝脏胶原沉积情况；荧光定量RT-PCR检测肝组织胶原蛋白Ⅲ在转录水平的表达；免疫组织化学和Western blotting测定肝脏Vimentin, E-cadherin和a-SMA等在蛋白水平的表达；小鼠生存期和生存状态观察,来评价MSCs对血吸虫性慢性肝纤维化的修复作用。③分离、纯化血吸虫卵并提取SEA,培养巨噬细胞并将其分成5组：阴性对照组、SEA组、SEA+MSCs上清组(MSCs组)、SEA+NRK-52E上清组(NRK-52E组)、SEA+DMEM组(DMEM组)。除阴性对照组巨噬细胞不做任何处理外,其他各组给予20μg/ml SEA诱导巨噬细胞活化12小时后,MSCs组、NRK-52E组和DMEM组撤SEA,分别给予MSCs培养48小时上清、NRK-52E培养48小时上清和DMEM培养液,继续培养。④显微镜观察细胞上清培养12小时后各组细胞的形态；实时荧光定量RT-PCR检测细胞上清培养12小时和24小时后巨噬细胞TNF-α的mRNA水平；Western blotting检测细胞上清培养12小时后TGF-β1的蛋白表达水平；MTT法测定细胞上清培养24小时和48小时后巨噬细胞增殖情况。
结果MSCs能显著提高小鼠生存率,移植8周后,MSCs组小鼠生存率为62.5%,而PBS组仅为12.5%(p<0.05)；移植第2周和第4周后,MSCs组小鼠脾脏指数分别为0.017±0.002和0.024±0.005,均显著低于PBS组的0.026±0.006和0.033±0.004(p<0.01),在移植2、4周后,PZQ+MSCs组小鼠脾脏指数亦均显著低于PZQ+PBS组；在移植第2周和第4周,MSCs组小鼠血清HA含量分别为319.43±21.36μg/ml和186.00±30.14μg/ml,均显著低于PBS组的388.25±45.68μg/ml和333.44±43.58μg/ml (p<0.05);在移植第2周和第4周,MSCs组小鼠血清TGF-β1水平分别为50.6±13.8 ng/ml和46.9±20.3 ng/ml,均显著低于PBS组的87.2±24.4 ng/ml和115.2±36.2 ng/ml (p<0.05); MSCs移植4周后,肝脏的组织学结构得到明显改善,且以PZQ+MSCs组改善更为显著,表现为炎症细胞浸润及胶原沉积均显著减少,虫卵结节的平均直径降低；移植4周后实时定量PCR检测到MSCs组Ⅲ型胶原mRNA的相对表达水平为阴性对照的1.82±0.84倍,低于PBS组的3.56±1.07倍(p<0.05), PZQ+MSCs组Ⅲ型胶原mRNA的相对表达为阴性对照的的1.06±0.34倍,远低于PZQ+PBS组的2.51±0.84(p<0.01)；移植4周后,免疫组化结果显示MSCs组,尤其是PZQ+MSCs组小鼠肝脏Vimentin阳性细胞数减少而E-cadherin阳性细胞数显著增多。Western blotting结果也提示,与PBS组比较,MSCs组小鼠肝脏Vimentin和α-SMA蛋白表达水平降低(p<0.05), PZQ+MSCs组α-SMA亦显著低于PZQ+PBS组。体内实验结果提示MSCs能缓解血吸虫性肝纤维化,与PZQ联合应用修复效果更好。
与NRK-52E上清和DMEM培养液比较,MSCs上清培养巨噬细胞12小时后,细胞变圆,体积明显较小,伪足较少。细胞培养上清作用12和24小时后,MSCs组TNF-α的mRNA水平为阴性对照组的1.0±0.4倍和1.0±0.5,显著低于NRE-52E组的10.4±3.9倍(p<0.05)和16.5±5.0倍(p<0.01),亦低于DMEM组的6.0±2.1倍和2.4±0.7倍(均p<0.05)。细胞培养上清作用12小时后,Western blotting结果显示MSCs组TGF-β1的表达显著低于SEA组.NRK-52E组和DMEM组。MSCs匕清作用48小时后,MTT测吸光度为0.22±0.05,显著低于NRK-52E组的0.53±0.02和DMEM组的0.31±0.03(均p<0.05)。体外结果表明,MSCs培养上清能抑制SEA诱导的巨噬细胞活化和增殖。结论MSCs能显著提高血吸虫性肝纤维化小鼠的生存率,有效缓解血吸虫性肝纤维化,与驱虫药吡喹酮联合应用能取得更好的治疗效果。其机制可能是通过诱导肝细胞间质-上皮转化和抑制巨噬细胞活化来修复肝损伤。结果提示,MSCs移植,尤其是和吡喹酮联合应用可以作为改善血吸虫性肝纤维化的有效措施。
Objective To observe the effect of administrating bone marrow stem cells (MSCs) alone or combining MSCs with praziquantel (PZQ) on repairing liver fibrosis induced by Schistosoma japonicum. The mechanisms were explored through in vivo and in vitro experiments, and which provide the experimental basis of MSCs transplantation on treating liver damage of Schistosoma japonicum.
Methods①iver fibrosis of mice was induced by repeated infection of Schistosoma japonicum. Mice in the experiment were divided into five groups as uninfected control, PBS group, MSCs group, PZQ+PBS group, PZQ+MSCs group. Each mouse in MSCs group and PZQ+MSCs group was transplanted with 5×105 MSCs through tail vein at the 9th and 10th week after infection. Each mouse in PZQ+PBS group and PZQ+MSCs group was administrated with 300 mg/kg PZQ through gastric gavage at the 9th week of infection.②Transforming growth factor-β1 (TGF-β1) and hyaluronic acid (HA) levels in serum were examined by ELISA and chemiluminescence assays at 2 and 4 weeks after first MSCs transplantation. The pathological change and collagen deposition were observed by hematoxylin-eosin (HE) staining and Masson's trichrome staining. Collagen type 3 mRNA expression was detected by real time quantitative RT-PCR. The protein expression of Vimentin, E-cadherin and a-SMA were tested by immunohistochemistry and western blotting. The survival time and general situation of mice were observed. The methods of above were used to evaluate the therapeutic effect of MSCs on fibrosis of Schistosoma japonicum and explore its mechanism.③Eggs of Schistosoma japonicum were isolated and purified and SEA was extracted. Macrophages were cultured and divided into five groups, which were negative control, SEA group, SEA+MSCs supernatant group (SEA group), SEA+NRK-52E supernatant group (NRK-52E group) and SEA+DMEM group (DMEM group). Macrophages in each group except negative control were induced by 20μg/ml SEA for 12 hours, then SEA was removed from MSC, NRK-52E and DMEM group, and replaced with MSCs supernatant, NRK-52E supernatant and DMEM respectively and went on culturing.④ppearance of macrophages in each group was observed by microscope after cultured with supernatant for 12 hours. The relative expression of tumor necrosis factor-α(TNF-α) mRNA in macrophages was detected by real-time quantitative RT-PCR after cultured with supernatant for 12 and 24 hours. The relative expression of protein TGF-β1 in macrophages was detected by western blotting after cultured with supernatant for 12 hours. Macrophages proliferation assay was tested by MTT after cultured with supernatant for 24 and 48 hours.
Results MSCs can prolong the survival time of mice infected with Schistosoma japonicum. The survival rate was 62.5% in MSCs group, but only 12.5% in PBS group after 8 weeks of transplantation (p<0.05). After transplanted for 2 and 4 weeks, the spleen indexes of mice in MSCs group were 0.017±0.002 and 0.024±0.005, much lower than that 0.026±0.006 and 0.033±0.004 in PBS group (p<0.01), and the spleen index was also much lower in PZQ+MSCs group than that in PZQ+PBS group. After 2 and 4 weeks transplantation, HA levels in serum of mice in MSCs group were 319.43±21.36μg/ml and 186.00±30.14μg/ml, much lower than 388.25±45.68μg/ml and 333.44±43.58μg/ml in PBS group (p<0.05). TGF-β1 levels in serum of mice were 5036±13.8 ng/ml and 46.9±20.3 ng/ml, lower than 87.2±24.4 ng/ml and 115.2±36.2 ng/ml in PBS group after 2 and 4 weeks of transplantation (p<0.05). After 4 weeks transplantation, the histological structure of livers in MSCs group was ameliorated greatly, especially in PZQ+MSCs group, which were expressed by the decreasing inflammatory cell infiltration, the reducing collagen deposition and the decreasing mean egg diameter. After transplanted with MSCs for 4 weeks, the collagen 3 mRNA expression in MSCs group was the 1.82±0.84 fold of uninfected control, lower than 3.56±1.07 fold in PBS group (p<0.05). And collagen 3 mRNA was 1.06±0.34 fold in PZQ+MSCs, also much lower than that 2.51±0.84 in PZQ+PBS group (p<0.01). After 4 weeks transplantation, the results of imrnunohistochemistry revealed that the Vimentin positive cells in livers of mice in MSCs group were much less than that in PBS group, Vimentin positive cells in PZQ+MSCs group were less than in PZQ+PBS group, too. But E-cadherin positive cells in livers of mice in MSCs group, especially in PZQ+MSCs group, were much more than that in PBS group. The proteins expression of Vimentin and a-SMA decreased in the liver of mice treated with MSCs. All there results revealed that MSCs were able to ameliorate Schistosoma japonicum-induced liver injury and this effect was enhanced by combining MSCs with conventional drug PZQ.
Comparing with SEA group, NRK-52E group, and DMEM group, macrophages in MSC group became rounder, smaller and had less pseudopodia after cultured with MSCs supernatant for 12 hours. After cultured with MSCs supernatant for 12 and 24 hours, TNF-αmRNA expression of macrophages in MSC group was 1.0±0.4 and 1.0±0.5 fold of negative control, much lower than 10.4±3.9 and 16.5±5.0 fold in NRE-52E group (12 hours, p<0.05; 24 hours, p＜0.01), also lower than 6.0±2.1 and 2.4±0.7 in DMEM group (all p<0.05). The result of western blotting revealed that after cultured with MSCs supernatant for 12 hours, the expression of TGF-β1 in macrophages in MSC group was weaker than in SEA group, NRK-52E group and DMEM group. After cultured with supernatant for 48 hours,A490 of macrophages in MSC group was 0.22±0.05, much lower than 0.53±0.02 in NRK-52E group and 0.31±0.03 in DMEM group (all p<0.05). Results in vitro suggest that MSCs supernatant inhibit activation and proliferation of macrophages which were induced by SEA of Schistosoma japonicum.
Conclusion MSC treatment relieves fibrosis of Schistosomiasis and achieves better therapeutic effects if combined MSCs with PZQ. The mechanism is that MSCs can induce mesenchymal-epithelial transition (MET) or inhibit activation of macrophages to relieve fibrosis in some degree. The results suggest us that MSCs transplantation especially combined with PZQ can be as an effective measure to ameliorate the liver fibrosis induced by Schistosoma japonicum.
方法①应用日本血吸虫尾蚴多次感染的方式建立血吸虫性肝纤维化的小鼠模型,并将小鼠分为5组：未感染对照组、PBS组、MSCs组、PZQ+PBS组、PZQ+MSCs组。在感染第9、10周,MSCs处理组每只小鼠分别给予5×105MSCs经尾静脉移植入肝损伤小鼠,PZQ处理组于感染第9周经灌胃给予300 mg/kg(?)比喹酮。②首次移植MSCs的第2、4周后分别应用ELISA和化学发光法检测血清中转化生长因子-β1 (transforming growth factor-β1, TGF-β1)和透明质酸(hyaluronic acid, HA)含量；病理切片苏木精-伊红染色法(HE)染色观察肝脏的组织学变化；Masson's三色染色观察肝脏胶原沉积情况；荧光定量RT-PCR检测肝组织胶原蛋白Ⅲ在转录水平的表达；免疫组织化学和Western blotting测定肝脏Vimentin, E-cadherin和a-SMA等在蛋白水平的表达；小鼠生存期和生存状态观察,来评价MSCs对血吸虫性慢性肝纤维化的修复作用。③分离、纯化血吸虫卵并提取SEA,培养巨噬细胞并将其分成5组：阴性对照组、SEA组、SEA+MSCs上清组(MSCs组)、SEA+NRK-52E上清组(NRK-52E组)、SEA+DMEM组(DMEM组)。除阴性对照组巨噬细胞不做任何处理外,其他各组给予20μg/ml SEA诱导巨噬细胞活化12小时后,MSCs组、NRK-52E组和DMEM组撤SEA,分别给予MSCs培养48小时上清、NRK-52E培养48小时上清和DMEM培养液,继续培养。④显微镜观察细胞上清培养12小时后各组细胞的形态；实时荧光定量RT-PCR检测细胞上清培养12小时和24小时后巨噬细胞TNF-α的mRNA水平；Western blotting检测细胞上清培养12小时后TGF-β1的蛋白表达水平；MTT法测定细胞上清培养24小时和48小时后巨噬细胞增殖情况。
结果MSCs能显著提高小鼠生存率,移植8周后,MSCs组小鼠生存率为62.5%,而PBS组仅为12.5%(p<0.05)；移植第2周和第4周后,MSCs组小鼠脾脏指数分别为0.017±0.002和0.024±0.005,均显著低于PBS组的0.026±0.006和0.033±0.004(p<0.01),在移植2、4周后,PZQ+MSCs组小鼠脾脏指数亦均显著低于PZQ+PBS组；在移植第2周和第4周,MSCs组小鼠血清HA含量分别为319.43±21.36μg/ml和186.00±30.14μg/ml,均显著低于PBS组的388.25±45.68μg/ml和333.44±43.58μg/ml (p<0.05);在移植第2周和第4周,MSCs组小鼠血清TGF-β1水平分别为50.6±13.8 ng/ml和46.9±20.3 ng/ml,均显著低于PBS组的87.2±24.4 ng/ml和115.2±36.2 ng/ml (p<0.05); MSCs移植4周后,肝脏的组织学结构得到明显改善,且以PZQ+MSCs组改善更为显著,表现为炎症细胞浸润及胶原沉积均显著减少,虫卵结节的平均直径降低；移植4周后实时定量PCR检测到MSCs组Ⅲ型胶原mRNA的相对表达水平为阴性对照的1.82±0.84倍,低于PBS组的3.56±1.07倍(p<0.05), PZQ+MSCs组Ⅲ型胶原mRNA的相对表达为阴性对照的的1.06±0.34倍,远低于PZQ+PBS组的2.51±0.84(p<0.01)；移植4周后,免疫组化结果显示MSCs组,尤其是PZQ+MSCs组小鼠肝脏Vimentin阳性细胞数减少而E-cadherin阳性细胞数显著增多。Western blotting结果也提示,与PBS组比较,MSCs组小鼠肝脏Vimentin和α-SMA蛋白表达水平降低(p<0.05), PZQ+MSCs组α-SMA亦显著低于PZQ+PBS组。体内实验结果提示MSCs能缓解血吸虫性肝纤维化,与PZQ联合应用修复效果更好。
与NRK-52E上清和DMEM培养液比较,MSCs上清培养巨噬细胞12小时后,细胞变圆,体积明显较小,伪足较少。细胞培养上清作用12和24小时后,MSCs组TNF-α的mRNA水平为阴性对照组的1.0±0.4倍和1.0±0.5,显著低于NRE-52E组的10.4±3.9倍(p<0.05)和16.5±5.0倍(p<0.01),亦低于DMEM组的6.0±2.1倍和2.4±0.7倍(均p<0.05)。细胞培养上清作用12小时后,Western blotting结果显示MSCs组TGF-β1的表达显著低于SEA组.NRK-52E组和DMEM组。MSCs匕清作用48小时后,MTT测吸光度为0.22±0.05,显著低于NRK-52E组的0.53±0.02和DMEM组的0.31±0.03(均p<0.05)。体外结果表明,MSCs培养上清能抑制SEA诱导的巨噬细胞活化和增殖。结论MSCs能显著提高血吸虫性肝纤维化小鼠的生存率,有效缓解血吸虫性肝纤维化,与驱虫药吡喹酮联合应用能取得更好的治疗效果。其机制可能是通过诱导肝细胞间质-上皮转化和抑制巨噬细胞活化来修复肝损伤。结果提示,MSCs移植,尤其是和吡喹酮联合应用可以作为改善血吸虫性肝纤维化的有效措施。
Objective To observe the effect of administrating bone marrow stem cells (MSCs) alone or combining MSCs with praziquantel (PZQ) on repairing liver fibrosis induced by Schistosoma japonicum. The mechanisms were explored through in vivo and in vitro experiments, and which provide the experimental basis of MSCs transplantation on treating liver damage of Schistosoma japonicum.
Methods①iver fibrosis of mice was induced by repeated infection of Schistosoma japonicum. Mice in the experiment were divided into five groups as uninfected control, PBS group, MSCs group, PZQ+PBS group, PZQ+MSCs group. Each mouse in MSCs group and PZQ+MSCs group was transplanted with 5×105 MSCs through tail vein at the 9th and 10th week after infection. Each mouse in PZQ+PBS group and PZQ+MSCs group was administrated with 300 mg/kg PZQ through gastric gavage at the 9th week of infection.②Transforming growth factor-β1 (TGF-β1) and hyaluronic acid (HA) levels in serum were examined by ELISA and chemiluminescence assays at 2 and 4 weeks after first MSCs transplantation. The pathological change and collagen deposition were observed by hematoxylin-eosin (HE) staining and Masson's trichrome staining. Collagen type 3 mRNA expression was detected by real time quantitative RT-PCR. The protein expression of Vimentin, E-cadherin and a-SMA were tested by immunohistochemistry and western blotting. The survival time and general situation of mice were observed. The methods of above were used to evaluate the therapeutic effect of MSCs on fibrosis of Schistosoma japonicum and explore its mechanism.③Eggs of Schistosoma japonicum were isolated and purified and SEA was extracted. Macrophages were cultured and divided into five groups, which were negative control, SEA group, SEA+MSCs supernatant group (SEA group), SEA+NRK-52E supernatant group (NRK-52E group) and SEA+DMEM group (DMEM group). Macrophages in each group except negative control were induced by 20μg/ml SEA for 12 hours, then SEA was removed from MSC, NRK-52E and DMEM group, and replaced with MSCs supernatant, NRK-52E supernatant and DMEM respectively and went on culturing.④ppearance of macrophages in each group was observed by microscope after cultured with supernatant for 12 hours. The relative expression of tumor necrosis factor-α(TNF-α) mRNA in macrophages was detected by real-time quantitative RT-PCR after cultured with supernatant for 12 and 24 hours. The relative expression of protein TGF-β1 in macrophages was detected by western blotting after cultured with supernatant for 12 hours. Macrophages proliferation assay was tested by MTT after cultured with supernatant for 24 and 48 hours.
Results MSCs can prolong the survival time of mice infected with Schistosoma japonicum. The survival rate was 62.5% in MSCs group, but only 12.5% in PBS group after 8 weeks of transplantation (p<0.05). After transplanted for 2 and 4 weeks, the spleen indexes of mice in MSCs group were 0.017±0.002 and 0.024±0.005, much lower than that 0.026±0.006 and 0.033±0.004 in PBS group (p<0.01), and the spleen index was also much lower in PZQ+MSCs group than that in PZQ+PBS group. After 2 and 4 weeks transplantation, HA levels in serum of mice in MSCs group were 319.43±21.36μg/ml and 186.00±30.14μg/ml, much lower than 388.25±45.68μg/ml and 333.44±43.58μg/ml in PBS group (p<0.05). TGF-β1 levels in serum of mice were 5036±13.8 ng/ml and 46.9±20.3 ng/ml, lower than 87.2±24.4 ng/ml and 115.2±36.2 ng/ml in PBS group after 2 and 4 weeks of transplantation (p<0.05). After 4 weeks transplantation, the histological structure of livers in MSCs group was ameliorated greatly, especially in PZQ+MSCs group, which were expressed by the decreasing inflammatory cell infiltration, the reducing collagen deposition and the decreasing mean egg diameter. After transplanted with MSCs for 4 weeks, the collagen 3 mRNA expression in MSCs group was the 1.82±0.84 fold of uninfected control, lower than 3.56±1.07 fold in PBS group (p<0.05). And collagen 3 mRNA was 1.06±0.34 fold in PZQ+MSCs, also much lower than that 2.51±0.84 in PZQ+PBS group (p<0.01). After 4 weeks transplantation, the results of imrnunohistochemistry revealed that the Vimentin positive cells in livers of mice in MSCs group were much less than that in PBS group, Vimentin positive cells in PZQ+MSCs group were less than in PZQ+PBS group, too. But E-cadherin positive cells in livers of mice in MSCs group, especially in PZQ+MSCs group, were much more than that in PBS group. The proteins expression of Vimentin and a-SMA decreased in the liver of mice treated with MSCs. All there results revealed that MSCs were able to ameliorate Schistosoma japonicum-induced liver injury and this effect was enhanced by combining MSCs with conventional drug PZQ.
Comparing with SEA group, NRK-52E group, and DMEM group, macrophages in MSC group became rounder, smaller and had less pseudopodia after cultured with MSCs supernatant for 12 hours. After cultured with MSCs supernatant for 12 and 24 hours, TNF-αmRNA expression of macrophages in MSC group was 1.0±0.4 and 1.0±0.5 fold of negative control, much lower than 10.4±3.9 and 16.5±5.0 fold in NRE-52E group (12 hours, p<0.05; 24 hours, p＜0.01), also lower than 6.0±2.1 and 2.4±0.7 in DMEM group (all p<0.05). The result of western blotting revealed that after cultured with MSCs supernatant for 12 hours, the expression of TGF-β1 in macrophages in MSC group was weaker than in SEA group, NRK-52E group and DMEM group. After cultured with supernatant for 48 hours,A490 of macrophages in MSC group was 0.22±0.05, much lower than 0.53±0.02 in NRK-52E group and 0.31±0.03 in DMEM group (all p<0.05). Results in vitro suggest that MSCs supernatant inhibit activation and proliferation of macrophages which were induced by SEA of Schistosoma japonicum.
Conclusion MSC treatment relieves fibrosis of Schistosomiasis and achieves better therapeutic effects if combined MSCs with PZQ. The mechanism is that MSCs can induce mesenchymal-epithelial transition (MET) or inhibit activation of macrophages to relieve fibrosis in some degree. The results suggest us that MSCs transplantation especially combined with PZQ can be as an effective measure to ameliorate the liver fibrosis induced by Schistosoma japonicum.
引文
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